Spot 14, also known as thyroid hormone-responsive Spot 14 (THRSP) or S14, is a primarily nuclear protein that is abundant in tissues active in long chain fatty acid synthesis, including lactating mammary gland (Cunningham, et al. (1998) Thyroid 8:815-825). It has been shown that the S14 gene is located on chromosome 11q13 and is overexpressed in most breast cancers (Moncur, et al. (1998) Proc. Natl. Acad. Sci. USA 95:6989-6994). Concordant overexpression of S14 and acetyl CoA-carboxylase, the rate-determining enzyme of long-chain fatty acid synthesis, indicates that S14 is a component of the lipogenic phenotype observed in aggressive breast cancers.
The lipogenic tumor phenotype is characterized by high rates of fatty acid synthesis, elevated tumor content of lipogenic enzymes such as fatty acid synthase (FAS), and dependence on lipogenesis for tumor cell growth (Kuhajda (2000) Nutrition 16:202-2). Cerulenin, a pharmacological inhibitor of fatty acid synthase has been shown to cause apoptosis of breast cancer cells (Pizer, et al. (1996) Cancer Res. 56:2745-2747), and inhibit the growth of human ovarian tumor cell xenografts in nude mice (Pizer, et al. (1996) Cancer Res. 56:1189-1193). Likewise, the anti-obesity drug Orlistat, also a FAS inhibitor, causes apoptosis of lipogenic prostate cancer cells in culture and in xenografts in immunodeficient mice (Kridel, et al. (2004) Cancer Res. 64:2070-2075).
In hepatocytes, S14 and lipogenic enzymes are inducible by insulin, glucose metabolism, and thyroid hormone (Cunningham, et al. (1998) supra). The lipogenic effects of insulin are substantially mediated at the gene level by sterol response element-binding protein 1c (SREBP-1c), a transcription factor that resides in the endoplasmic reticulum until insulin activates its translocation to the Golgi, where the active fragment is released by proteolysis, permitting transit to the nucleus to activate gene transcription (Foretz, et al. (1999) Proc. Natl. Acad. Sci. USA 96:12737-12742; Rawson (2003) Nat. Rev. Mol. Cell. Biol. 4:631-640). As in the liver, SREBP-1c may be the major driver of lipogenic gene expression. This issue has been addressed in studies of breast cancer specimens (Yang, et al. (2003) Exp. Cell Res. 282:132-137), colon cancer specimens and cells (Li, et al. (2000) Exp. Cell. Res. 261:159-165), and prostate cancer cells (Swinnen, et al. (1997) Proc. Natl. Acad. Sci. USA 94:12975-12980; Swinnen, et al. (2000) Oncogene 19:5173-5181; Heemers, et al. (2001) Mol. Endocrinol. 15:1817-1828). The studies of breast and colon cancer correlated expression of FAS and SREBP-1c, but did not include mechanistic experiments. Studies in prostate cancer cells, however, directly demonstrated dependence of androgen- and growth factor-induced expression of FAS on SREBP-1c. Moreover, processing of the extranuclear SREBP-1c precursor was increased by androgen induction of SREBP cleavage-activating protein (SCAP), the protein responsible for escorting SREBP-1c to the Golgi, where proteolytic activation occurs. In contrast to the enhancement of SREBP-1c processing by androgen in prostate cancer cells, however, no increase was observed in nuclear SREBP-1c content in progestin-treated T47D cells demonstrating S14 gene induction (Heemers, et al. (2000) Biochem. Biophys. Res. Comm. 269:209-212).
A number of other proteins have been identified which may accelerate the growth of breast cancer cells. Such proteins include p53, a transcriptional regulator with tumor suppressor properties, nm23, a putative metastasis suppressor, and several families of cell surface growth factor receptors and their cognate ligands, including the epidermal growth factor (EGF) receptor superfamily, the insulin-like growth factor (IGF-1) family, and the fibroblast growth factor (FGF) family. For example, HER2, a receptor with close similarity to EGF-Receptor, also known as c-erBb-2 (Coussens, et al. (1985) Science 230:1132-1139; Yamamoto, et al. (1986) Nature 319:230-234; King, et al. (1985) Nature 307:521-527) has been identified. This receptor was also isolated as the rat oncogene neu, an oncogene responsible for chemically-induced rat glioblastomas (Padhy, et al. (1982) Cell 28:865-871; Schechter, et al. (1984) Nature 312:513-516; Bargmann, et al. (1986) Nature 319:226-230). HER2/erbB-2 is known to be amplified and overexpressed in about 25% of human breast cancers (Slamon, et al. (1987) Science 235:177-182; Slamon, et al. (1989) Science 244:707-712).